Our previous experiments have shown that increased tricarboxylic acid cycle activities by acetate infusion are associated with hyperdynamic circulatory state. We will continue to investigate the effects of increased tricarboxylic acid cycle intermediates on cardiac output and systemic hemodynamics. Tricarboxylic acid cycle intermediates such as alpha-keto-glutarate, succinate and malate will be infused. In addition, malonate and arsenate will be administered to block the tricarboxylic acid cycle and cause an accumulation of tricarboxylic acid cyclic metabolites. These experiments will allow us to identify those intermediates which are linked to the increases in cardiac output and regional blood flows. We previously have shown that beta-adrenergic blockade reduces the cardiac output responses to hypoxemia and exercise. To determine whether the peripheral vascular resistance is similarly controlled by adrenergic tone, experiments will be carried out to determine whether changes in regional blood flows during hypoxemia and hypoxia are affected by alpha- and beta-adrenergic blockade. In addition, because plasma renin activity has been shown to increase during exercise and hypoxemia, we will study whether the renin-angiotensin system plays an important role in these circulatory responses by administering saralasin (angiotensin antagonist) of SQ 20881 (angiotensin converting enzyme inhibitor).